CN108096195B - Method for preparing azilsartan solid dispersion by supercritical anti-solvent method - Google Patents

Method for preparing azilsartan solid dispersion by supercritical anti-solvent method Download PDF

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CN108096195B
CN108096195B CN201810013894.6A CN201810013894A CN108096195B CN 108096195 B CN108096195 B CN 108096195B CN 201810013894 A CN201810013894 A CN 201810013894A CN 108096195 B CN108096195 B CN 108096195B
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azilsartan
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crystallization kettle
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王志祥
宋雅琴
徐文博
陈震
缪虹刚
王为彦
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China Pharmaceutical University
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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Abstract

The invention discloses a method for preparing azilsartan solid dispersion by a supercritical anti-solvent method, which comprises the following steps: step S1, dissolving the azilsartan and the water-soluble carrier in an organic solvent to obtain an azilsartan-carrier mixed solution; step S2, adding CO2Introducing into a crystallization kettle, and adjusting the temperature and pressure in the crystallization kettle; step S3, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and simultaneously introducing the azilsartan-carrier mixed solution prepared in the step S1 into the crystallization kettle; step S4, after the azilsartan-carrier solution is introduced, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and releasing the pressure after a period of time; opening the crystallization kettle to collect the azilsartan solid dispersion after the pressure in the crystallization kettle is reduced to the atmospheric pressure; wherein the water-soluble carrier is PVP-K30. By the method, the azilsartan is dispersed in PVP-K30 in an amorphous form, so that the dissolution rate of the azilsartan can be improved, and the stability of the azilsartan can be improved.

Description

Method for preparing azilsartan solid dispersion by supercritical anti-solvent method
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for preparing azilsartan solid dispersion by a supercritical anti-solvent method.
Background
Azilsartan (Azilsartan) of the molecular formula C25H20N4O5The trade name AZILVA, manufactured by Wushu, JapanThe field pharmaceutical company (Takeda) developed and marketed in japan at1 month 2012 and the FDA approved marketing at 25/2 month 2011. Azilsartan, as a new generation of angiotensin II receptor blocker for treating hypertension, can competitively and reversibly cut off the combination of angiotensin II and AT1 receptor, thereby reducing blood pressure. Azilsartan belongs to a poorly soluble drug, and has a solubility of less than 9 mug/ml in water and a low solubility in organic solvents. After the drug is absorbed, the action of the drug depends mainly on the water solubility of the active ingredient and the permeability of the active ingredient to the mucous membrane of the viscera, and the dissolution is the rate-limiting step of the absorption process. Therefore, the dissolving rate of the azilsartan is improved, the absorption of the azilsartan in a human body is improved, and the azilsartan injection has important significance for improving the absorption of the azilsartan in the human body.
Solid dispersion technology is a solubilization technology which is based on the principle of dispersing a drug in a molecular, colloidal, microcrystalline or amorphous state in a suitable solid carrier material to form a solid mass. The carrier materials commonly used for preparing the solid dispersion comprise water-soluble carrier materials, insoluble carrier materials and enteric carrier materials; the preparation method comprises a melting method, a solvent-melting method, a grinding method and the like. In recent years, a novel supercritical anti-solvent (SAS) technology is gradually utilized due to its excellent characteristics; the supercritical fluid has good dissolubility, small viscosity, small surface tension and good mass transfer effect, and the form of the solid dispersion can be controlled by adjusting parameters such as pressure, temperature and the like; compared with the traditional method, the supercritical anti-solvent method has the advantages of mild operation conditions, small organic solvent residue, environmental protection and good uniformity of the obtained product, and is particularly suitable for preparing heat-sensitive or bioactive medicines.
The supercritical anti-solvent method is that a solvent can be well dissolved with a supercritical fluid, but the solubility of a solute in the supercritical fluid is low, when the supercritical fluid and the solution are contacted with each other, the fluid is diffused into the solution, so that the solution is rapidly expanded, the solubility of the solute in the solution is rapidly reduced, a high supersaturation degree is formed instantly, and the solute is promoted to be separated out.
The chinese patent application with publication number CN103755694A discloses a method for preparing azilsartan raw material by supercritical method, the azilsartan prepared by the method has small particle size, and the water solubility of azilsartan is improved to a certain extent. However, the parameters provided by this method are not suitable for the preparation of solid dispersions of azilsartan.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for preparing azilsartan solid dispersion by a supercritical anti-solvent method, so that azilsartan is highly dispersed in a carrier PVP-K30.
The above object of the present invention is achieved by the following technical solutions:
a method for preparing azilsartan solid dispersion by a supercritical anti-solvent method comprises the following steps:
step S1, dissolving the azilsartan and the water-soluble carrier in an organic solvent to obtain an azilsartan-carrier mixed solution;
step S2, adding CO2Introducing into a crystallization kettle, and adjusting the temperature and pressure in the crystallization kettle;
step S3, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and simultaneously introducing the azilsartan-carrier mixed solution prepared in the step S1 into the crystallization kettle;
step S4, after the azilsartan-carrier solution is introduced, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and releasing the pressure after a period of time; opening the crystallization kettle to collect the azilsartan solid dispersion after the pressure in the crystallization kettle is reduced to the atmospheric pressure;
wherein the water-soluble carrier is PVP-K30, and the sequence of the step S1 and the step S2 does not exist.
Preferably, the organic solvent is a mixed solvent of acetone, dichloromethane and dimethyl sulfoxide, and the three solvents are mixed according to a volume ratio of 1:1: 0.01.
Preferably, the mass ratio of the azilsartan and the PVP-K30 is 1:1-1: 5.
Preferably, the mass concentration of the azilsartan in the mixed solution is 3.5-9.5 g/L.
Preferably, the temperature in the crystallization kettle is adjusted to 35-55 ℃ and the pressure in the crystallization kettle is adjusted to 9-17MPa in the step S2.
Preferably, the volume flow rate of the mixed solution introduced into the crystallization kettle in the step S3 is 0.9-3.0 mL/min.
Preferably, CO is used in step S32The flow rate of (2) is 1-4L/min.
Preferably, the period of time in step S4 is 0.5-2 h.
Preferably, the mass ratio of the azilsartan to the PVP-K30 in the mixed solution is 1:3, and the mass concentration of the azilsartan is 5.0 g/L; the temperature in the crystallization kettle is 40 ℃, and the pressure is 11 MPa; the volume flow of the mixed solution is 0.9 mL/min; CO22The flow rate of the gas introduced into the crystallization kettle is 2.5L/min; the pressure is relieved after 1.5 h.
The invention has the advantages that:
the azilsartan solid dispersion can be successfully prepared by a supercritical anti-solvent method, and the azilsartan is proved to be dispersed in PVP-K30 in an amorphous form by observing a DSC (differential scanning calorimetry) spectrum; in vitro dissolution experiment results show that compared with the bulk drugs, the azilsartan solid dispersion has obviously improved dissolution performance, and the specific expression is that the cumulative dissolution rate of the azilsartan solid dispersion can reach more than 95% through dissolution rate determination of 60min, the recovery rate is high, and the cumulative dissolution rate of the bulk drugs is less than 10%; in addition, the stability of the azilsartan can be improved by dispersing the azilsartan in the carrier. Compared with the prior art, the method has prominent substantive characteristics and remarkable progress.
Drawings
Fig. 1 is a schematic structural diagram of experimental equipment, wherein: 1-CO2A storage tank; 2-CO2A pump; 3-a cooling device; 4-solution storage tank; 5-high performance liquid pump; 6-crystallization kettle; 7-solvent recovery kettle; 8-flow meter.
FIG. 2 is a graph showing the influence relationship between the drug carrier ratio and the 60min cumulative dissolution rate and recovery rate of the azilsartan solid dispersion;
FIG. 3 is a graph showing the influence of crystallization kettle pressure on the 60min cumulative dissolution rate and recovery rate of the azilsartan solid dispersion;
FIG. 4 is a graph showing the influence of the crystallization kettle temperature on the 60min cumulative dissolution rate and recovery rate of the azilsartan solid dispersion;
FIG. 5 is a graph showing the influence of mass concentration on the 60-min cumulative dissolution rate and recovery rate of the azilsartan solid dispersion;
FIG. 6 is a relation of influence of solution volume flow on 60min cumulative dissolution rate and recovery rate of the azilsartan solid dispersion;
fig. 7 is a DSC analysis of azilsartan solid dispersion;
fig. 8 is a dissolution rate comparison graph of azilsartan crude drug, physical mixture and solid dispersion of azilsartan.
Detailed Description
The following detailed description of the present invention is provided in connection with the accompanying drawings and examples, but not intended to limit the scope of the invention.
Example 1: single factor method for investigating influence of each parameter value range on accumulative dissolution rate and recovery rate
Laboratory instruments and materials
The main instruments used in the experiment are shown in table 1, and the main raw materials and auxiliary materials and reagents are shown in table 2.
TABLE 1 Main Instrument
Device name Model number Manufacturer of the product
Supercritical particle preparation system Helix American applied separations Inc
Series1500 high pressure infusion pump Helix American applied separations Inc
Air compression pump TYW-2 Suzhou city same electromechanical company Limited
Low-temperature constant-temperature tank SDC-6 Nanjing Xinchen Biotechnology Ltd
Ultraviolet visible spectrophotometer UV-1800 Shimadzu Japan Ltd
Intelligent dissolution experimental instrument ZRS-8L Tianjin Tianda Tianfa science and technology Co Ltd
Analytical balance BS124S Beijing Sadolis Instrument systems, Inc
TABLE 2 Main and auxiliary materials and reagents
Name of reagent Specification of Manufacturer of the product
Azilsartan 98％ Jinan Li De medicine technology Co., Ltd
Acetone (II) AR Nanjing chemical reagents Ltd
Methylene dichloride AR Shanghai Lingfeng Chemicals Co., Ltd
Dimethyl sulfoxide AR Chemical reagent for national medicine group
PVP-K30 ≥98％ Shanghai-derived leaf Zhiyuan Biotech Co Ltd
CO2 >99％ Nanjing Shangyuan industrial gas plant
Distilled water - Homemade by Chinese pharmaceutical university
Phosphate buffer pH5.8 Laboratory self-control
Experimental device and operation flow
The experimental flow is shown in fig. 1, and the operation flow is specifically as follows:
(1) all valves of the instrument are ensured to be in a closed state, and equipment and various detectors are installed. Opening the low-temperature constant-temperature tank and setting the temperature; simultaneously starting the main engine and setting CO2Preheating temperature, heating temperature of crystallization kettle, CO at outlet2Heating the temperature, then opening a heating switch of the crystallization kettle, and opening CO after the temperature reaches a set value2Inlet valve, CO2The mixture is preheated by a preheating device through a pressure pump and enters the crystallization kettle from the top of the crystallization kettle.
(2) After the pressure in the crystallization kettle reaches a pressure set value and is stable, opening CO at the bottom of the crystallization kettle2While passing CO through the outlet valve2Micro-valve control of CO2At a flow rate of CO2The flow is stabilized in a certain range, and the air in the crystallization kettle is exhausted.
(3) And spraying the prepared solution into the crystallization kettle from the top of the crystallization kettle through a nozzle by a high performance liquid pump.
(4) After the sample introduction is finished through the steps, continuously introducing CO2And (5) removing residual solvent for 0.5-2 h. Finally CO is turned off2And (5) a steel cylinder starts to release pressure, and after the pressure is released to the atmospheric pressure, the crystallization kettle is opened, and the product is collected.
Single factor experiments: effect of drug Carrier ratio
Under the conditions that the crystallization pressure is 11MPa, the crystallization temperature is 40 ℃, the mass concentration of the azilsartan is 5.0g/L, and the volume flow of the solution is 0.9mL/min, the influence on the cumulative dissolution rate of the azilsartan solid dispersion in 60min and the influence on the recovery rate are examined when the ratios of the drug carriers are respectively 1:1, 1:2, 1:3, 1:4 and 1: 5. The results are shown in fig. 2, the 60min cumulative dissolution rates were 32.34%, 65.31%, 97.16%, 97.88% and 99.07%, respectively, and the recovery rates were 69.62%, 80.91%, 60.83%, 63.47% and 74.09%, respectively. The solvent is a mixed solvent of acetone, dichloromethane and dimethyl sulfoxide, and is mixed according to the volume ratio of 1:1: 0.01.
Along with the increase of the drug carrier ratio, the recovery rate basically does not change greatly, and the cumulative dissolution rate after 60min gradually increases and tends to be stable. The analysis reason is that the medicament is well dispersed in the carrier along with the increase of the proportion of the carrier, the wetting effect of the carrier on the medicament is gradually enhanced, and the dissolution rate is gradually increased, but the wetting effect of the carrier on the medicament reaches a certain limit along with the increase of the proportion of the carrier, so the dissolution rate of the medicament tends to be stable.
Single factor experiments: influence of crystallization pressure
Under the conditions that the crystallization temperature is 40 ℃, the azilsartan mass concentration is 5g/L, the solution volume flow is 0.9mL/min and the drug carrier ratio is 1:1, the influence of crystallization pressures of 9, 11, 13, 15 and 17MPa on the accumulative dissolution rate of the azilsartan solid dispersion in 60min and the influence of the recovery rate are examined. The results are shown in fig. 3, wherein the 60min cumulative dissolution rates are 36.82%, 32.34%, 24.63%, 56.63% and 30.55%, and the recovery rates are 79.47%, 69.62%, 77.08%, 70.58% and 38.72%, respectively. The solvent is a mixed solvent of acetone, dichloromethane and dimethyl sulfoxide, and the three solvents are mixed according to the volume ratio of 1:1: 0.01.
With the increase of the crystallization pressure, the 60min cumulative dissolution rate firstly decreases and then increases, and the cumulative dissolution rate is highest at 15 MPa; the reason may be that the solute solubility of the fluid increases with increasing pressure, resulting in a decrease in the solute precipitation rate, a decrease in the drug dispersion on the carrier, and a decrease in dissolution rate, but as the pressure continues to increase, the CO increases2The dissolving capacity to the solvent is rapidly increased, the supersaturation degree of the system is rapidly increased, and the medicine is precipitated and dispersed on the carrier more uniformly. As the pressure increased, the recovery rate was essentially unchanged and then decreased to 38.72%, possibly over-pressure, CO2The dissolving capacity for solute and solvent is greatly improved, so that the medicine is carried out along with CO2, and the recovery rate is reduced.
Single factor experiments: influence of crystallization temperature
Under the conditions that the crystallization pressure is 11MPa, the azilsartan mass concentration is 5.0g/L, the solution volume flow is 0.9mL/min and the drug carrier ratio is 1:1, the influence of crystallization temperatures of 35, 40, 45, 50 and 55 ℃ on the accumulative dissolution rate of the azilsartan solid dispersion in 60min and the influence of the recovery rate are examined. The results are shown in fig. 4, wherein the 60min cumulative dissolution rates are 51.22%, 32.34%, 35.40%, 30.89% and 35.09%, and the recovery rates are 39.42%, 69.92%, 73.17%, 79.50% and 87.75%, respectively. The solvent is a mixed solvent of acetone, dichloromethane and dimethyl sulfoxide, and the three solvents are mixed according to the volume ratio of 1:1: 0.01.
With the increase of the crystallization temperature, the azilsartan solid dispersion tends to be stable after 60min accumulated dissolution rate is reduced, and the recovery rate tends to gradually increase. This occurs because, with increasing temperature, CO2The solubility of the solute is gradually increased, the supersaturation degree of the solute is reduced, and the solute cannot be well precipitated and dispersed on the carrier, so that the dissolution rate is reduced.
Single factor experiments: effect of Azilsartan Mass concentration
Under the conditions that the crystallization pressure is 11MPa, the crystallization temperature is 40 ℃, the volume flow of the solution is 0.9mL/min, and the ratio of the drug carriers is 1:1, the influence on the accumulative dissolution rate of the azilsartan solid dispersion in 60min and the influence on the recovery rate are examined when the azilsartan mass concentration is respectively 3.5, 5.0, 6.5, 8.0 and 9.5 g/L. The results are shown in fig. 5, the 60min cumulative dissolution rates are 32.55%, 32.34%, 23.62%, 23.10% and 30.08%, and the recovery rates are 78.84%, 69.92%, 53.55%, 65.83% and 86.23%, respectively. The solvent is a mixed solvent of acetone, dichloromethane and dimethyl sulfoxide, and the three solvents are mixed according to the volume ratio of 1:1: 0.01.
With the increase of the azilsartan mass concentration, the change of the 60-min accumulated dissolution rate of the azilsartan solid dispersion is not obvious, the approximate trend is that the dissolution rate is firstly reduced and then increased, and the recovery rate is also firstly reduced and then increased. Probably because the drug is in CO with increasing mass concentration2The solubility of the drug is increased, which causes poor dispersion of the drug on the carrier, reduced dissolution rate, and CO-associated drug2Taking out; however, as the mass concentration increases, the solvent is in CO2The solubility in (b) increases, resulting in an increase in the supersaturation degree of the solute, and the precipitation of the solute to form a solid dispersion.
Single factor experiments: influence of the volume flow of the solution
Under the conditions that the crystallization pressure is 11MPa, the crystallization temperature is 40 ℃, the azilsartan mass concentration is 5.0g/L and the drug carrier ratio is 1:1, the influence on the accumulative dissolution rate of the azilsartan solid dispersion in 60min and the influence on the recovery rate are examined when the volume flow of the solution is 0.9, 1.5, 2.0, 2.5 and 3.0ml/min respectively. The results are shown in fig. 6, in which the 60min cumulative dissolution rates were 32.34%, 18.08%, 48.05%, 32.95% and 35.79%, respectively, and the recovery rates were 69.62%, 83.50%, 86.56%, 70.71% and 72.56%, respectively. The solvent is acetone, dichloromethane and dimethyl sulfoxide which are mixed according to the volume ratio of 1:1: 0.01.
With the increase of the volume flow of the solution, the cumulative dissolution rate of the azilsartan solid dispersion is increased after the decrease in 60min, and the recovery rate is increased after the decrease in the recovery rate. When the volume flow of the solution is low, the speed of the solution entering the kettle through the nozzle is too low, the initial liquid drop is enlarged, the atomization effect is weakened, the dispersion effect of the medicine on the carrier is weakened, the dissolution rate is reduced, the sample introduction time is long, and the production efficiency is low. When the volume flow of the solution is increased, the solution enters the kettle to be atomized, the mass transfer effect is increased, the dispersion effect is enhanced, the dissolution rate is increased, and CO is generated2The dissolving capacity for the solute becomes weak and the recovery rate increases.
Example 2: optimized parameter for preparing azilsartan solid dispersion by using supercritical anti-solvent method
The method for preparing the azilsartan solid dispersion by using a supercritical anti-solvent method comprises the following steps:
step S1, dissolving the azilsartan and the water-soluble carrier in an organic solvent to obtain an azilsartan-carrier mixed solution;
step S2, adding CO2Introducing into a crystallization kettle, and adjusting the temperature and pressure in the crystallization kettle;
step S3, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and simultaneously introducing the azilsartan-carrier mixed solution prepared in the step S1 into the crystallization kettle;
step S4, after the azilsartan-carrier solution is introduced, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and releasing the pressure after a period of time; when the pressure in the crystallization kettle dropsOpening the crystallization kettle to collect the azilsartan solid dispersion after the pressure reaches the atmospheric pressure;
wherein the water-soluble carrier is PVP-K30, the mass ratio of the azilsartan to the PVP-K30 is 1:3, the organic solvent is a mixed solvent of acetone, dichloromethane and dimethyl sulfoxide, and the three are mixed according to the volume ratio of 1:1: 0.01. The mass concentration of the azilsartan in the mixed solution is 5.0 g/L; the temperature in the crystallization kettle is 40 ℃, and the pressure is 11 MPa; the volume flow of the mixed solution is 0.9 mL/min; CO22The flow rate is 2.5L/min; the pressure is relieved after 1.5 h.
Characterization and analysis of the obtained azilsartan-PVP-K30 solid dispersion:
DSC analysis
The appearance is white powder, DSC analysis shows that the melting point peak of azilsartan is 212.1 ℃ from A, PVP-K30 has a wider absorption peak at 50-90 ℃ due to strong hygroscopicity, and the absorption peak is a dehydration peak; in the physical mixture, absorption peaks of azilsartan and PVP-K30 exist, while in the solid dispersion, only a dehydration peak of PVP-K30 exists, and an endothermic peak of azilsartan disappears, which indicates that no drug crystal exists at the moment, and the drug exists in an amorphous form in PVP-K30.
In vitro dissolution test
Respectively weighing bulk drugs, physical mixtures and solid dispersions which are equivalent to 40mg of azilsartan, taking 900ml of buffer solution with pH 5.8 as a dissolution medium according to a dissolution determination method (the second method of appendix of 2015 edition in Chinese pharmacopoeia), rotating at 100r/min, operating according to the method, taking 10ml of the solution when 5, 10, 15, 20, 25, 30, 45 and 60min respectively, simultaneously adding 10ml of the dissolution medium with the same temperature, filtering the solution through a 0.22 mu m filter membrane, determining the peak area of the solution under the condition of 250nm, calculating the concentration of the solution according to a standard curve equation, and calculating the cumulative dissolution of the solution. The result is shown in fig. 8, compared with the bulk drug and the physical mixture, the dissolution rate is greatly improved, the cumulative dissolution rate within 60min reaches 97.16% (recovery rate 80.91%), and the cumulative dissolution rate within 60min of the bulk drug and the physical mixture is less than 10%, which shows that the release rate of azilsartan is obviously improved. Meanwhile, it is known to those skilled in the art that the stability can be improved by dispersing azilsartan in a carrier.
Discussion of results
(1) Experiments prove that the azilsartan solid dispersion can be successfully prepared by a supercritical anti-solvent method, and the azilsartan is proved to be dispersed in PVP-K30 in an amorphous form by observing a DSC (differential scanning calorimetry) spectrum;
(2) in vitro dissolution experiment results show that compared with the bulk drugs, the azilsartan solid dispersion has significantly improved dissolution performance, and specifically, the accumulated dissolution rate of the azilsartan solid dispersion can reach more than 95% and is less than 10% through dissolution rate determination of 60 min. The dissolution performance of the azilsartan solid dispersion is greatly improved;
(3) the stability of the azilsartan can be improved by dispersing the azilsartan in the carrier.
Comparative example 1:
on the basis of example 2, the solvent was replaced by ethanol.
The product was white powder in appearance, and DSC analysis showed that azilsartan could not be completely and uniformly dispersed in PVP-K30, and some azilsartan remained physically mixed in the product, as shown in comparison 1 in fig. 7.
Comparative example 2:
on the basis of example 2, the solvent was replaced by ethanol-dichloromethane-DMSO (1:1: 0.01).
As a result, a powdery substance could not be produced, the product agglomerated together, and the surface was wet.
In conclusion, the azilsartan solid dispersion can be successfully prepared by a supercritical anti-solvent method, and the observation of DSC (differential scanning calorimetry) spectrum proves that the azilsartan is dispersed in PVP-K30 in an amorphous form; in vitro dissolution experiment results show that compared with the bulk drugs, the azilsartan solid dispersion has obviously improved dissolution performance, and the specific expression is that the cumulative dissolution rate of the azilsartan solid dispersion can reach more than 95% through dissolution rate determination of 60min, the recovery rate is high, and the cumulative dissolution rate of the bulk drugs is less than 10%; in addition, the stability of the azilsartan can be improved by dispersing the azilsartan in the carrier. Compared with the prior art, the method has prominent substantive characteristics and remarkable progress.
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.

Claims (1)

1. A method for preparing azilsartan solid dispersion by a supercritical anti-solvent method is characterized by comprising the following steps:
step S1, dissolving the azilsartan and the water-soluble carrier in an organic solvent to obtain an azilsartan-carrier mixed solution;
step S2, adding CO2Introducing into a crystallization kettle, and adjusting the temperature and pressure in the crystallization kettle;
step S3, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and simultaneously introducing the azilsartan-carrier mixed solution prepared in the step S1 into the crystallization kettle;
step S4, after the azilsartan-carrier solution is introduced, continuously introducing CO2Maintaining the temperature and the pressure in the crystallization kettle unchanged, and releasing the pressure after a period of time; opening the crystallization kettle to collect the azilsartan solid dispersion after the pressure in the crystallization kettle is reduced to the atmospheric pressure;
wherein the water-soluble carrier is PVP-K30, the mass ratio of the azilsartan to the PVP-K30 is 1:3, the organic solvent is a mixed solvent of acetone, dichloromethane and dimethyl sulfoxide, and the three are mixed according to the volume ratio of 1:1: 0.01; the mass concentration of the azilsartan in the mixed solution is 5.0 g/L; the temperature in the crystallization kettle is 40 ℃, and the pressure is 11 MPa; the volume flow of the azilsartan-carrier mixed solution introduced into the crystallization kettle is 0.9 mL/min; CO22The flow rate is 2.5L/min; the pressure is relieved after 1.5 h.
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